For those with severe mental illness, cognitive deficits are the core impediment to their independent living. Treatments to improve cognition are urgently needed, but no new pharmacotherapies have been approved in over a decade. Psychotherapeutic interventions remain helpful but exhibit only moderate effect sizes. Because these interventions predominantly aid learning through positive reinforcement strategies, augmenting such learning with pharmacotherapies should synergistically enhance the effectiveness of those interventions. Striatal dopamine D1 receptors contribute to positive reinforcement learning but directly targeting these receptors produce undesirable side-effects. Activating the a7 nicotinic acetylcholine receptor (nAChR) indirectly activates striatal dopamine D1 receptors, providing a link between the a7 nAChR and positive reinforcement learning. This project will identify dopaminergic and nAChR pro-learning treatments and determine whether their effects are mediated by striatal dopamine D1 receptors. Reward- and punishment- related learning will be measured using the probabilistic learning (PL) task. The PL task rewards and punishes responding to both target and non-target stimuli. Selecting the target stimulus is normally rewarded (80%) but occasionally punished (20%). For the non-target stimulus, the reward/punishment schedule is reversed. Thus importantly, the PL task measures the speed at which the animal acquires contingencies during uncertainty and modulates its behavior as a function of reward history. Selecting the same side after a reward (win-stay) is beneficial only after a target response, while shifting after a loss is beneficial only after a non-target response reflecting good reward- and punishment-associative learning respectively. The indirect dopamine agonist levodopa improves PL via enhancing reward-associative learning in both healthy humans and Parkinson's patients. Similarly, we demonstrated an amphetamine- (another indirect dopamine agonist) and nicotine- (a general nAChR agonist) induced improvement of PL in mice via enhancing reward-associative learning. Specific Aim 1 will identify pro-learning doses of amphetamine, nicotine, and the selective a7 nAChR agonist PNU 282987, utilizing amphetamine as a positive control. Specific Aim 2 will determine the mechanism(s) underlying pro-learning effects of amphetamine, nicotine, and PNU via combined studies with pharmacological inactivation of: 1) a7 nAChRs (methyllycaconitine); 2) dopamine D1-like (SCH 23390); and 3), D2-like receptors (haloperidol); plus 4) Genetic null-mutation of the a7 nAChR, and 5) Adeno- Associated Viral (AAV)-induced suppression of striatal dopamine D1 receptors. Thus, using complementary techniques, we will confirm that a7 nAChR activation improves learning via enhancing reward-associative learning, a mechanism that is a7 nAChR-dependent and that occurs as a result of indirect activation of striatal dopamine D1 receptors. Pro-learning treatments identified here could be tested in healthy humans, potentially augmenting psychotherapeutic interventions and improving the lives of patients with mental illness.